Combined treatment with ruxolitinib and MK-2206 inhibits the JAK2/STAT5 and PI3K/AKT pathways via apoptosis in MDA-MB-231 breast cancer cell line

  • Mol Biol Rep. 2022 Nov 4. doi: 10.1007/s11033-022-08034-4.
Esin Guvenir Celik  1  2  3 ,  Onur Eroglu  4  5
Affiliations
  • 1. Department of Molecular Biology and Genetics, Faculty of Science, Bilecik Seyh Edebali University, Bilecik, Turkey. [email protected].
  • 2. Biotechnology Research and Application Center, Bilecik Seyh Edebali University, Bilecik, Turkey. [email protected].
  • 3. Department of Molecular Biology and Genetics, Institute of Graduate Education, Bilecik Şeyh Edebali University, Bilecik, Turkey. [email protected].
  • 4. Department of Molecular Biology and Genetics, Faculty of Science, Bilecik Seyh Edebali University, Bilecik, Turkey.
  • 5. Biotechnology Research and Application Center, Bilecik Seyh Edebali University, Bilecik, Turkey.
PMID: 36331743 DOI: 10.1007/s11033-022-08034-4
Abstract

Background: Due to deficiencies in the expression of hormone receptors, such as PR, ER and HER2, it is challenging to treat triple-negative breast Cancer, which does not respond to single targeted therapy. Ruxolitinib is a Janus kinase (JAK)1/JAK2 Inhibitor. MK-2206 is an allosteric Akt Inhibitor. Due to the limited activities of ruxolitinib and MK-2206 for monotherapy, the need for cotreatment with Other drugs has emerged. This study is the first to examine the effects of ruxolitinib and MK-2206 cotreatment on Apoptosis and JAK2/STAT5 and PI3K/Akt signaling in MDA-MB-231 breast Cancer cells. Additionally, this work aimed to decrease the side effects of ruxolitinib and increase its Anticancer effects with MK-2206 cotreatment.

Methods and results: Cell viability was reduced in a dose- and time-dependent manner after exposure to ruxolitinib, MK-2206 or both for 48 h, as shown by MTT assay. Ruxolitinib had a synergistic antiproliferative effect, as demonstrated by colony formation and wound healing assays. The effects of ruxolitinib, MK-2206 and their combination on Apoptosis, as well as PI3K/Akt and JAK/STAT signaling, were examined by western blot analyses. Cotreatment with ruxolitinib and MK-2206 reduced proliferation with the dual inhibition of JAK2/STAT5 and PI3K/Akt signaling by decreasing PI3K, Akt, JAK2, STAT5, Caspase-9, Caspase-7, PARP, c-Myc, and Bcl-2 and increasing P53 and PTEN protein expression.

Conclusions: Our results revealed the roles of P53 and PTEN in the regulation of Apoptosis and the PI3K/Akt and JAK2/STAT5 signaling pathways. The dual inhibition of JAK2/STAT5 and PI3K/Akt may reduce metastasis by decreasing tumor cell survival.

Keywords
Apoptosis; JAK2/STAT5; MK-2206; PI3K/AKT; Ruxolitinib; TNBC.
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